Blueprint Genetics / Tests / Panels / Ear, Nose & Throat / Comprehensive Hearing Lo...

Comprehensive Hearing Loss and Deafness Panel

Summary
  • Is a 288 gene panel that includes assessment of non-coding variants.

  • In addition, it also includes the maternally inherited mitochondrial genome.
    Is ideal for patients with a clinical suspicion of syndromic or non-syndromic genetic hearing loss.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

288

Test code

EA0501

Panel size

Large

CPT code *
81430, 81431, 81460, 81465
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Summary

The Blueprint Genetics Comprehensive Hearing Loss and Deafness Panel (test code EA0501):

Read about our accreditations, certifications and CE-marked IVD medical devices here.

Test Specific Strength

Our panel assay enables the detection of common deletions in GJB6 such as ((~309 kb del (GJB6-D13S1830) and ~232 kb del (GJB6-D13S1854)).

ICD codes

Refer to the most current version of ICD-10-CM manual for a complete list of ICD-10 codes.

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Please see Sample Requirements for accepted saliva kits)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

Read more about our sample requirements here.

Subpanel description

This comprehensive panel includes genes from the following panels: Alport Syndrome Panel, Branchio-Oto-Renal (BOR) Syndrome Panel, Non-Syndromic Hearing Loss Panel, Pendred Syndrome Panel, Stickler Syndrome Panel, Syndromic Hearing Loss Panel, Usher Syndrome Panel and Waardenburg Syndrome Panel.

Hearing loss is a genetically very heterogenous group of phenotypes varying in severity and causes. Non-syndromic sensorineural hearing loss is a partial or total loss of hearing that occurs without other associated clinical findings. In syndromic hearing loss, symptoms affecting other parts of the body occur in addition to hearing impairment or deafness. Sensorineural hearing loss can be unilateral or bilateral and it can be stable or progressive. In addition, the loss may appear with various intensivity to high, middle or low tones. It is estimated that approximately 60-80% of congenital hearing loss is genetic in origin. Some 60%-to-70% of congenital hereditary hearing impairnment have a non-syndromic origin. The prevalence of non-syndromic hearing loss is 3-4:10,000 neonates and increases with age. In many populations, mutations in GJB2 are the most prevalent explaining up to 50% of all non-syndromic hearing losses. Altogether syndromic hearing loss accounts for 20% to 30% of congenital hearing loss and deafness and the combined prevalence of syndromic hearing loss is approximately 1-2:10,000.

Genes in the Comprehensive Hearing Loss and Deafness Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABHD12 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 16 20
ABHD5 Chanarin-Dorfman syndrome AR 11 39
ACOX1 Peroxisomal acyl-CoA oxidase deficiency AD/AR 15 26
ACTB* Baraitser-Winter syndrome AD 55 60
ACTG1* Deafness, Baraitser-Winter syndrome AD 27 47
ADCY1 Deafness AR 1 1
ADGRV1 Usher syndrome, type IIC AR 71 236
AIFM1 Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome XL 27 31
ALMS1* Alström syndrome AR 197 302
AMMECR1 Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis XL 4 5
ANKH Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type AD 13 20
ANLN Focal segmental glomerulosclerosis AD 2 4
ARSG Usher syndrome, type IV AR 1 1
ATP2B2 Sensorineural hearing loss AD 3 7
ATP6V0A4 Renal tubular acidosis, distal AR 16 84
ATP6V1B1 Renal tubular acidosis with deafness AR 15 56
ATP6V1B2 Deafness, congenital, with onychodystrophy, autosomal dominant, Zimmermann-Laband syndrome 2 AD 6 3
BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1 AR 42 37
BDP1* Hearing loss AD/AR 1 1
BSND Sensorineural deafness with mild renal dysfunction, Bartter syndrome AR 10 20
BTD Biotinidase deficiency AR 170 247
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3 AD/AR 37 80
CABP2 Deafness AR 1 6
CACNA1D Primary aldosteronism, seizures, and neurologic abnormalities, Sinoatrial node dysfunction and deafness AD/AR 7 8
CATSPER2* Male Infertility, Deafness AR 2 7
CCDC50 Deafness AD 1 4
CD151 Raph blood group, Nephropathy with pretibial epidermolysis bullosa and deafness AR 1 3
CD164 Deafness, autosomal dominant 66 AD 1 1
CDC14A Deafness, autosomal recessive 105 AR 7 9
CDC42* Takenouchi-Kosaki syndrome, Noonan-syndrome like phenotype AD 11 9
CDH23 Deafness, Usher syndrome, type 1D AR 94 358
CDK9 AR 1
CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 35 81
CEACAM16 Deafness AD/AR 4 4
CEP250 Cone rod dystrophy and hearing loss AR 5
CEP78 Cone rod dystrophy and hearing loss AR 7 9
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 276 860
CHSY1 Temtamy preaxial brachydactyly syndrome AR 6 16
CIB2 Deafness, Usher syndrome type IJ AR 5 18
CISD2* Wolfram syndrome 2 AR 2 4
CLDN14 Deafness AR 11 12
CLIC5 Deafness AR 1 2
CLPP Deafness AR 4 13
CLRN1 Retinitis pigmentosa, Usher sydnrome, type 3A AR 24 39
COCH Deafness AD 14 29
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 34 94
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 29 57
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 180 561
COL4A3 Alport syndrome, Hematuria, benign familial AD/AR 123 264
COL4A4 Alport syndrome AD/AR 110 232
COL4A5 Alport syndrome XL 704 992
COL4A6 Deafness, with cochlear malformation XL 11 5
COL9A1 Multiple epiphyseal dysplasia type 6 (EDM6), Stickler syndrome, type IV AD/AR 9 6
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL9A3 Multiple epihyseal dysplasia type 3 (EDM3), Stickler syndrome recessive type AD/AR 10 14
CRYM Deafness AD 2 4
DCAF17 Woodhouse-Sakati syndrome AR 14 14
DCDC2 Deafness, Nephronophthisis, Sclerosing cholangitis, neonatal AR 13 9
DFNA5 Deafness AD 7 13
DFNB31 Usher syndrome, type 2D, Deafness, autosomal recessive 31 AR 12 31
DFNB59 Deafness AR 12 20
DIABLO Deafness AD 1 2
DIAPH1 Seizures, cortical blindness, and microcephaly syndrome (SCBMS), Deafness, autosomal dominant 1 AD/AR 10 15
DIAPH3 Non-syndromic sensorineural deafness AD 1 9
DLX5 Split-hand/foot malformation with sensorineural hearing loss, Split-hand/foot malformation AD/AR 3 9
DMXL2 Deafness, autosomal dominant, 71, Polyendocrine-polyneuropathy syndrome, Epileptic encephalopathy, early infantile AD/AR 2 6
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 9 20
DSPP Dentin dysplasia, Dentinogenesis imperfecta, Deafness, with dentinogenesis imperfecta AD 11 53
EDN3 Hirschsprung disease, Central hypoventilation syndrome, congenital, Waardenburg syndrome AD/AR 7 21
EDNRA Mandibulofacial dysostosis with alopecia AD 2 4
EDNRB Hirschsprung disease, ABCD syndrome, Waardenburg syndrome AD/AR 12 66
EFTUD2 Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromic AD 45 99
EIF3F Intellectual disability, autosomal recessive AR
ELMOD3 Deafness AR 1 2
EPS8 Deafness AR 2 2
EPS8L2 Deafness, autosomal recessive 106 AR 2 2
ESPN* Deafness, Deafness, autosomal recessive 36 AD/AR 12 15
ESRRB Deafness AR 12 19
EYA1 Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome AD 56 218
EYA4 Dilated cardiomyopathy (DCM), Deafness, autosomal dominant 10 AD 15 28
FAM136A* Sensorineural hearing loss AD 1 2
FAM65B Deafness AR 1 2
FDXR Auditory neuropathy and optic atrophy AR 5 19
FGF3 Deafness, congenital with inner ear agenesis, microtia, and microdontia AR 13 20
FGFR2 Apert syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Lacrimoauriculodentodigital syndrome, Beare-Stevenson cutis gyrata syndrome, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, Craniofacial-skeletal-dermatological dysplasia, Crouzon syndrome, Bent bone dysplasia AD 100 154
FGFR3 Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN AD/AR 54 77
FITM2 Dystonia, Deafness AR 1
FOXC1 Axenfeld-Rieger syndrome, Iridogoniodysgenesis, Peters anomaly AD 46 135
FOXI1 Pendred syndrome, Enlarged vestibular aqueduct AR 1 11
GATA3 Hypomagnesemia, renal, Hypoparathyroidism, sensorineural deafness, and renal dysplasia AD 22 86
GDF6 Microphthalmia, isolated 4, Microphthalmia, isolated, with coloboma 6, Coloboma, ocular, Klippel-Feil syndrome 1, autosomal dominant, Leber congenital amaurosis 17 AD/AR 9 21
GIPC3 Deafness AR 9 20
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD/AR 31 107
GJB2 Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome AD/AR/Digenic 133 405
GJB3 Deafness, Erythrokeratodermia variabilis et progressiva 1, Deafness, autosomal dominant 2B AD/AR 11 40
GJB6 Deafness, autosomal dominant 3B, Ectodermal dysplasia, hidrotic (Clouston syndrome), Deafness, autosomal recessive 1B AD/AR 10 33
GPSM2 Deafness, Chudley-McCullough syndrome AR 18 11
GREB1L Congenital anomalies of the kidney and urinary tract, Renal hypodysplasia/aplasia 1 AD 15 36
GRHL2 Ectodermal dysplasia/short stature syndrome, Deafness, autosomal dominant 28, Corneal dystrophy, posterior polymorphous AD/AR 12 12
GRXCR1 Deafness AR 8 9
GRXCR2 Deafness AR 1 2
HARS Charcot-Marie-Tooth disease, axonal, type 2W, Usher syndrome, type 3B AD/AR 6 12
HARS2 Perrault syndrome AR 7 3
HGF Deafness AR 4 10
HOMER2 Deafness AD 2 1
HOXA2 Microtia, hearing impairment, and cleft palate AR 3 5
HOXB1 Facial paresis, hereditary congenital AR 3 6
HSD17B4 Perrault syndrome, D-bifunctional protein deficiency AR 60 99
ILDR1 Deafness AR 8 27
KARS Charcot-Marie-Tooth disease, Deafness, autosomal recessive AR 9 23
KCNE1 Long QT syndrome, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 11 46
KCNJ10 Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct AR/Digenic 13 29
KCNQ1 Short QT syndrome, Long QT syndrome, Atrial fibrillation, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 298 631
KCNQ4 Deafness AD 28 37
KIT Gastrointestinal stromal tumor, Piebaldism AD 79 116
KITLG Hyperpigmentation with or without hypopigementation, familial progressive, Skin/hair/eye pigmentation, variation in, 7 AD 6 10
KMT2D Kabuki syndrome AD 350 670
LARS2 Perrault syndrome, Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) AR 14 14
LHFPL5 Deafness AR 7 10
LHX3 Pituitary hormone deficiency, combined AR 9 16
LMX1A Hearing loss AD/AR 1 4
LOXHD1 Deafness, autosomal recessive 77 AR 26 60
LRP2 Donnai-Barrow syndrome, Faciooculoacousticorenal syndrome AR 24 38
LRTOMT Deafness AR 7 17
MAN2B1 Mannosidosis, alpha B, lysosomal AR 63 149
MANBA Mannosidosis, lysosomal AR 16 19
MARVELD2 Deafness AR 9 17
MASP1 3MC syndrome AR 11 22
MCM2 Deafness, autosomal dominant 70 AD 3 1
MET Deafness, Renal cell carcinoma, papillary, Osteofibrous dysplasia, susceptibility to AD/AR 20 34
MGP Keutel syndrome AR 5 8
MIR96 Deafness AD 2 4
MITF Tietz albinism-deafness syndrome, Waardenburg syndrome, Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD) AD/AR 32 58
MPZL2 Sensorineural hearing loss AR 4
MSRB3 Deafness AR 5 2
MT-ATP6 Neuropathy, ataxia, and retinitis pigmentosa, Leber hereditary optic neuropathy, Ataxia and polyneuropathy, adult-onset, Cardiomyopathy, infantile hypertrophic, Leigh syndrome, Striatonigral degeneration, infantile, mitochondrial Mitochondrial 19
MT-ATP8 Cardiomyopathy, apical hypertrophic, and neuropathy, Cardiomyopathy, infantile hypertrophic Mitochondrial 4
MT-CO1 Myoglobinuria, recurrent, Leber hereditary optic neuropathy, Sideroblastic anemia, Cytochrome C oxidase deficiency, Deafness, mitochondrial Mitochondrial 17
MT-CO2 Cytochrome c oxidase deficiency Mitochondrial 8
MT-CO3 Cytochrome c oxidase deficiency, Leber hereditary optic neuropathy Mitochondrial 9
MT-CYB Mitochondrial 69
MT-ND1 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia Mitochondrial 21
MT-ND2 Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 6
MT-ND3 Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 7
MT-ND4 Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 11
MT-ND4L Leber hereditary optic neuropathy Mitochondrial 2
MT-ND5 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 19
MT-ND6 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Oncocytoma, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 16
MT-RNR1 Deafness, mitochondrial Mitochondrial 3
MT-RNR2 Chloramphenicol toxicity/resistance Mitochondrial 2
MT-TA Mitochondrial 4
MT-TC Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 3
MT-TD Mitochondrial 1
MT-TE Diabetes-deafness syndrome, Mitochondrial myopathy, infantile, transient, Mitochondrial myopathy with diabetes Mitochondrial 5
MT-TF Myoclonic epilepsy with ragged red fibers, Nephropathy, tubulointerstitial, Encephalopathy, mitochondrial, Epilepsy, mitochondrial, Myopathy, mitochondrial, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 7
MT-TG Mitochondrial 3
MT-TH Mitochondrial 4
MT-TI Mitochondrial 7
MT-TK Myoclonic epilepsy with ragged red fibers, Leigh syndrome Mitochondrial 5
MT-TL1 Cytochrome c oxidase deficiency, Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Diabetes-deafness syndrome, Cyclic vomiting syndrome, SIDS, susceptibility to Mitochondrial 14
MT-TL2 Mitochondrial multisystemic disorder, Progressive external ophthalmoplegia, Mitochondrial Myopathy, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 5
MT-TM Leigh syndrome, Mitochondrial multisystemic disorder Mitochondrial 1
MT-TN Progressive external ophthalmoplegia, Mitochondrial multisystemic disorder Mitochondrial 3
MT-TP Mitochondrial 2
MT-TQ Mitochondrial multisystemic disorder Mitochondrial 2
MT-TR Encephalopathy, mitochondrial Mitochondrial 2
MT-TS1 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 10
MT-TS2 Mitochondrial multisystemic disorder Mitochondrial 2
MT-TT Mitochondrial 5
MT-TV Hypertrophic cardiomyopathy (HCM), Leigh syndrome, Mitochondrial multisystemic disorder, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 3
MT-TW Leigh syndrome, Myopathy, mitochondrial Mitochondrial 8
MT-TY Mitochondrial multisystemic disorder Mitochondrial 4
MYH14 Peripheral neuropathy, myopathy, hoarseness, and hearing loss, Deafness, autosomal dominant 4 AD 7 44
MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17 AD 25 117
MYO15A Deafness, autosomal recessive 3 AR 97 235
MYO3A Deafness AR 9 22
MYO6 Deafness, autosomal dominant, 22, Deafness, autosomal recessive 37 AD/AR 24 68
MYO7A Deafness, autosomal dominant 11, Usher syndrome, type I, Deafness, autosomal recessive 2 AD/AR 239 515
NARS2 Combined oxidative phosphorylation deficiency AR 12 12
NDP Exudative vitreoretinopathy, Norrie disease XL 31 167
NDRG1 Charcot-Marie-Tooth disease AR 6 8
NEFL Charcot-Marie-Tooth disease AD 24 40
NF2 Schwannomatosis, Neurofibromatosis AD 66 433
NLRP3 Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome, Familial cold-induced autoinflammatory syndrome 1, Deafness AD 20 136
NOG Tarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximal, Brachydactyly type B2 AD 20 63
NR2F1 Bosch-Boonstra optic atrophy syndrome AD 23 34
OPA1 Optic atrophy, Optic atrophy 1, Optic atrophy with or without deafness, Ophthalmoplegia, myopathy, ataxia, and neuropathy, Behr synrome, Mitochondrial DNA depletion syndrome 14 AD/AR 96 390
OSBPL2 Deafness AD 2 3
OTOA#* Deafness AR 19 28
OTOF Neuropathy, Deafness AR 107 163
OTOG Deafness AR 18 3
OTOGL Deafness, autosomal recessive 84B AR 26 23
P2RX2 Deafness AD 2 4
PAX1 Otofaciocervical syndrome 2 AR 2 10
PAX3 Craniofacial-deafness-hand syndrome, Waardenburg syndrome AD/AR 54 149
PCDH15 Deafness, Usher syndrome, type 1D AR/Digenic 113 118
PCGF2 AD 1
PDE1C Hearing loss AD 2 2
PDZD7# Deafness, autosomal recessive AR 11 19
PEX1 Heimler syndrome, Peroxisome biogenesis factor disorder 1A, Peroxisome biogenesis factor disorder 1B AR 112 134
PEX11B Zellweger syndrome, Peroxisome biogenesis disorder AR 5 7
PEX12 Zellweger syndrome, Peroxisome biogenesis disorder AR 43 37
PEX13 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 9 10
PEX14 Peroxisome biogenesis factor disorder 14, Zellweger syndrome AR 5 4
PEX2 Zellweger syndrome, Peroxisome biogenesis disorder AR 16 18
PEX26 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 13 27
PEX5 Adrenoleukodystrophy, neonatal, Rhizomelic chondrodysplasia punctata, Zellweger syndrome, Peroxisome biogenesis disorder AR 8 14
PEX6 Heimler syndrome, Peroxisome biogenesis disorder 4A, Peroxisome biogenesis disorder 4B AR 58 107
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 44 53
PHYH Refsum disease AR 12 36
PISD AR
PMP22 Neuropathy, inflammatory demyelinating, Roussy-Levy syndrome, Dejerine-Sottas disease, Neuropathy, hereditary, with liability to pressurve palsies, Charcot-Marie-Tooth disease AD/AR 49 165
PNPT1* Combined oxidative phosphorylation deficiency, 13, Deafness, autosomal recessive 70 AR 11 13
POLR1C# Treacher Collins syndrome AR 17 21
POLR1D Treacher Collins syndrome AD/AR 9 26
POU3F4 Deafness XL 25 80
POU4F3 Deafness AD 9 33
PRPS1* Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Deafness, X-linked 1 XL 27 32
PTPRQ Deafness, autosomal dominant 73, Deafness, autosomal recessive 84 AD/AR 10 34
RAI1 Smith-Magenis syndrome AD 37 112
RDX* Deafness, autosomal recessive 24 AR 6 10
REST Fibromatosis, gingival, 5 AD 3 16
RMND1* Combined oxidative phosphorylation deficiency AR 17 15
ROR1 Deafness, autosomal recessive 108 3 2
RPS6KA3 Coffin-Lowry syndrome, Mental retardation XL 65 171
S1PR2 Deafness, autosomal recessive 68 AR 2 3
SALL1* Townes-Brocks syndrome 1 AD 31 87
SALL4 Acro-renal-ocular syndrome, Duane-radial ray/Okihiro syndrome AD 21 56
SEMA3E CHARGE syndrome AD 1 4
SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome AR 22 52
SERPINB6 Deafness AR 2 3
SH3TC2 Mononeuropathy of the median nerve, Charcot-Marie-Tooth disease AR 63 89
SIX1 Deafness, Branchiootic syndrome, Branchiootorenal syndrome AD 11 19
SIX2 1 9
SIX5 Branchiootorenal syndrome AD 3 10
SLC17A8 Deafness AD 1 8
SLC19A2 Thiamine-responsive megaloblastic anemia syndrome AR 14 51
SLC22A4 Hearing loss AR 2
SLC26A4 Deafness, Pendred syndrome, Enlarged vestibular aqueduct AR 181 548
SLC26A5 Deafness, autosomal recessive 61 AR 2 7
SLC29A3 Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis AR 17 25
SLC33A1* Congenital cataracts, hearing loss, and neurodegeneration, Spastic paraplegia 42, autosomal dominant AD/AR 6 7
SLC44A4 Deafness, autosomal dominant, 72 1
SLC4A11 Cryohydrocytosis, Corneal dystrophy, Fuchs endothelial 4, Corneal endothelial dystrophy 2, autosomal recessive, Corneal endothelial dystrophy and perceptive deafness AD/AR 22 95
SLC52A2 Brown-Vialetto-Van Laere syndrome AR 27 25
SLC52A3 Fazio-Londe disease, Brown-Vialetto-Van Laere syndrome AR 30 42
SLITRK6 Deafness and myopia AR 3 5
SMAD4 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia AD 179 143
SMPX Deafness XL 8 14
SNAI2 Waardenburg syndrome, Piebaldism AR 2 4
SOX10 Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease, Kallmann syndrome AD 56 148
SPATA5 Developmental delay with or without dysmorphic facies and autism, Epilepsy, hearing loss, and mental retardation syndrome (EHLMRS) AR 27 27
STAG2 Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder XL 6 14
STRC#* Deafness AR 31 85
SUCLA2 Mitochondrial DNA depletion syndrome AR 9 29
SUCLG1 Mitochondrial DNA depletion syndrome AR 12 28
SYNE4 Deafness AR 6 2
SYT2* Myasthenic syndrome, congenital 7, presynaptic AD 3 3
TBC1D24 Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome, Deafness, autosomal dominant, 65, Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16, Deafness, autosomal recessive 86 AD/AR 43 55
TBL1X Congenital hypothyroidism, Hearing loss 2 8
TBX1 Conotruncal anomaly face syndrome AD 17 72
TCOF1 Treacher Collins syndrome AD 50 330
TECTA Deafness, autosomal dominant 8/12, Deafness, autosomal recessive 21 AD/AR 36 120
TFAP2A Branchiooculofacial sydrome AD 23 42
TIMM8A* Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia XL 11 21
TJP2 Cholestasis, progressive familial intrahepatic, Hypercholanemia, familial, Deafness, autosomal dominant 51 AD/AR 25 27
TMC1 Deafness, autosomal dominant 36, Deafness, autosomal recessive 7 AD/AR 33 91
TMEM126A Optic atrophy AR 3 1
TMEM132E Hearing loss AR 1
TMIE Deafness AR 9 10
TMPRSS3 Deafness AR 25 82
TNC Deafness AD 3 6
TPRN# Deafness, autosomal recessive 79 AR 6 12
TRIOBP Deafness AR 22 40
TRMU Liver failure, infantile, Reversible infantile respiratory chain deficiency AR 20 21
TRRAP Developmental delay with or without dysmorphic facies and autism AD 19
TSHZ1 Aural atresia, congenital AD 2 4
TSPEAR AR 2 7
TUBB4B Leber congenital amaurosis, Hearing loss AD 2 3
TYR* Albinism, oculocutaneous AR 77 441
UBR1 Johanson-Blizzard syndrome AR 11 71
USH1C Deafness, Usher syndrome, type IC AR 45 51
USH1G Usher syndrome, type 1G AR 13 32
USH2A Retinitis pigmentosa 39, Usher syndrome, type 2A AR 401 1169
VCAN Wagner disease AD 11 19
WBP2 Deafness, autosomal recessive 107 AR 3 3
WFS1 Wolfram syndrome, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41 AD/AR 69 362
XYLT2 Spondyloocular syndrome AR 2 10
*

Some, or all, of the gene is duplicated in the genome. Read more.

#

The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests.

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Mitomap databases.

Non-coding variants covered by Comprehensive Hearing Loss and Deafness Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
AIFM1 ChrX:129274636 c.697-44T>G NM_004208.3
AIFM1 ChrX:129299753 c.-123G>C NM_004208.3 rs724160014
ANKH Chr5:14871567 c.-11C>T NM_054027.4
BCS1L Chr2:219524871 c.-147A>G NM_004328.4
BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855
BTD Chr3:15683399 c.310-15delT NM_000060.2 rs587783008
BTD Chr3:15687154 c.*159G>A NM_000060.2 rs530872564
CDKN1C Chr11:2905209 c.*5+20G>T NM_000076.2 rs760540648
CHD7 Chr8:61734568 c.2836-15C>G NM_017780.3
CHD7 Chr8:61757794 c.5051-15T>A NM_017780.3
CHD7 Chr8:61763034 c.5405-18C>A NM_017780.3 rs199981784
CHD7 Chr8:61763035 c.5405-17G>A NM_017780.3 rs794727423
CHD7 Chr8:61763039 c.5405-13G>A NM_017780.3 rs1131690787
CLRN1 Chr3:150660197 c.254-649T>G NM_001195794.1 rs976853535
COL11A1 Chr1:103386637 c.3744+437T>G NM_080629.2
COL11A1 Chr1:103488576 c.1027-24A>G NM_080629.2
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL2A1 Chr12:48379984 c.1527+135G>A NM_001844.4
COL4A3 Chr2:228145145 c.2224-11C>T NM_000091.4
COL4A3 Chr2:228168708 c.4028-27A>G NM_000091.4
COL4A3 Chr2:228173092 c.4462+457C>G NM_000091.4
COL4A3 Chr2:228173596 c.4463-18dupA NM_000091.4 rs769590145
COL4A4 Chr2:227875240 c.4334-23A>G NM_000092.4
COL4A5 ChrX:107813924 c.385-719G>A NM_033380.2 rs104886396
COL4A5 ChrX:107816792 c.466-12G>A NM_033380.2 rs104886414
COL4A5 ChrX:107820077 c.609+875G>T NM_033380.2
COL4A5 ChrX:107821295 c.646-12_646-11delTT NM_033380.2 rs104886436
COL4A5 ChrX:107834930 c.1423+57dupC NM_033380.2 rs104886328
COL4A5 ChrX:107838719 c.1424-20T>A NM_033380.2 rs281874668
COL4A5 ChrX:107842994 c.1948+894C>G NM_033380.2
COL4A5 ChrX:107845097 c.2042-18A>G NM_033380.2 rs104886341
COL4A5 ChrX:107849932 c.2245-40A>G NM_033380.2
COL4A5 ChrX:107849958 c.2245-14T>A NM_033380.2
COL4A5 ChrX:107852872 c.2395+2750A>G NM_033380.2
COL4A5 ChrX:107908726 c.3374-11C>A NM_033380.2 rs104886387
COL4A5 ChrX:107933678 c.4529-2300T>G NM_033380.2
COL4A5 ChrX:107935633 c.4529-345A>G NM_033380.2
COL4A5 ChrX:107938272 c.4821+121T>C NM_033380.2 rs104886423
COL4A5 ChrX:107938337 c.4822-152dupT NM_033380.2
COL4A5 ChrX:107938346 c.4822-151_4822-150insT NM_033380.2 rs397515494
DCAF17 Chr2:172305176 c.322-14delC NM_025000.3 rs201494527
DFNA5 Chr7:24746007 c.991-15_991-13delTTC NM_004403.2 rs727505273
DIAPH3 Chr13:60738072 c.-172G>A NM_001042517.1
DIAPH3 Chr13:60738073 c.-173C>T NM_001042517.1
EDN3 Chr20:57875743 c.-125G>A NM_000114.2
EDN3 Chr20:57875849 c.-19C>A NM_000114.2 rs375594972
EYA1 Chr8:72156939 c.1051-12T>G NM_000503.4
EYA1 Chr8:72211483 c.640-15G>A NM_000503.4
EYA4 Chr6:133833847 c.1282-12T>A NM_004100.4
EYA4 Chr6:133833997 c.1341-19T>A NM_004100.4
FGFR2 Chr10:123099960 c.*139411C>T .
FOXC1 Chr6:1610252 c.-429C>G NM_001453.2 rs77888940
GJB2 Chr13:20763744 c.-22-2A>C NM_004004.5 rs201895089
GJB2 Chr13:20766920 c.-23+2T>A NM_004004.5
GJB2 Chr13:20766921 c.-23+1G>A NM_004004.5 rs80338940
GJB2 Chr13:20766922 c.-23G>T NM_004004.5 rs786204734
GJB2 Chr13:20767158 c.-259C>T NM_004004.5
GJB2 Chr13:20767159 c.-260C>T NM_004004.5
GRHL2 Chr8:102505149 c.20+133delA NM_024915.3
GRHL2 Chr8:102505272 c.20+257delT NM_024915.3
GRHL2 Chr8:102505561 c.20+544G>T NM_024915.3
GRXCR1 Chr4:42965170 c.627+19A>T NM_001080476.2 rs201824235
HGF Chr7:81384504 c.482+1991_482+2000delGATGATGAAA NM_000601.4 rs900334407
HGF Chr7:81384516 c.482+1986_482+1988delTGA NM_000601.4
HSD17B4 Chr5:118837725 c.1285-11C>G NM_001199291.1 rs779466683
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
KCNQ1 Chr11:2484803 rs2074238
KMT2D Chr12:49428461 c.10356-12G>A NM_003482.3
MYO3A Chr10:26409593 c.1777-12G>A NM_017433.4
MYO6 Chr6:76593963 c.2417-1758T>G NM_004999.3
MYO7A Chr11:76839534 c.-48A>G NM_000260.3
MYO7A Chr11:76893448 c.3109-21G>A NM_000260.3
MYO7A Chr11:76915107 c.5327-14T>G NM_000260.3
MYO7A Chr11:76915110 c.5327-11A>G NM_000260.3 rs397516316
MYO7A Chr11:76919448 c.5857-27_5857-26insTTGAG NM_000260.3
NDP ChrX:43818099 c.-207-1G>A NM_000266.3
NDP ChrX:43832545 c.-208+5G>A NM_000266.3
NDP ChrX:43832548 c.-208+2T>G NM_000266.3
NDP ChrX:43832549 c.-208+1G>A NM_000266.3
NDP ChrX:43832685 c.-343A>G NM_000266.3 rs895911086
NDP ChrX:43832722 c.-391_-380delCTCTCTCTCCCTinsGTCTCTC NM_000266.3
NDP ChrX:43832724 c.-396_-383delTCCCTCTCTCTCTC NM_000266.3 rs770996360
NF2 Chr22:30050946 c.516+232G>A NM_000268.3
OPA1 Chr3:193334932 c.449-34dupA NM_130837.2
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
PAX3 Chr2:223085913 c.958+28A>T NM_181459.3
PCDH15 Chr10:56560684 c.-29+1G>C NM_001142763.1
PEX6 Chr6:42933858 c.2301-15C>G NM_000287.3 rs267608236
PEX6 Chr6:42933952 c.2300+28G>A NM_000287.3 rs267608237
PEX7 Chr6:137143759 c.-45C>T NM_000288.3 rs267608252
PMP22 Chr17:15162523 c.79-13T>A NM_000304.3
REST Chr4:57793760 c.983-2247C>G NM_005612.4
RPS6KA3 ChrX:20191268 c.1228-279T>G NM_004586.2
RPS6KA3 ChrX:20213274 c.326-11A>G NM_004586.2
SERAC1 Chr6:158576548 c.92-165C>T NM_032861.3
SERAC1 Chr6:158576622 c.92-239G>C NM_032861.3
SH3TC2 Chr5:148406329 c.2873-14T>A NM_024577.3
SH3TC2 Chr5:148422415 c.386-15G>A NM_024577.3
SLC26A4 Chr7:107301201 c.-103T>C NM_000441.1 rs60284988
SLC26A4 Chr7:107301244 c.-60A>G NM_000441.1 rs545973091
SLC26A4 Chr7:107301301 c.-4+1G>C NM_000441.1
SLC26A4 Chr7:107301305 c.-4+5G>A NM_000441.1 rs727503425
SLC26A4 Chr7:107323842 c.918+45_918+47delCAA NM_000441.1
SLC26A4 Chr7:107330533 c.1150-35_1150-28delTTTGTAGG NM_000441.1
SLC26A4 Chr7:107334836 c.1264-12T>A NM_000441.1
SLC26A4 Chr7:107336364 c.1438-7dupT NM_000441.1 rs754734032
SLC26A4 Chr7:107341513 c.1708-27_1708-11delTAAGTAACTTGACATTT NM_000441.1
SLC26A4 Chr7:107350439 c.2090-52_2090-49delCAAA NM_000441.1
SLC29A3 Chr10:73122778 c.*413G>A NM_018344.5
SLC4A11 Chr20:3211931 c.1077+26_1077+44delCGGCAGGGTCGGCGGGGGC NM_001174090.1
SLC52A2 Chr8:145582843 c.-110-1G>A NM_024531.4
SNAI2 Chr8:49833972 c.-149_-148delCGinsTA NM_003068.4
SOX10 Chr22:38379877 c.-84-2A>T NM_006941.3
SOX10 Chr22:38412215 c.-31954C>T NM_006941.3 rs606231342
SOX10 Chr22:38412781 c.-32520C>G NM_006941.3 rs533778281
TBX1 Chr22:19743578 c.-777C>T NM_080647.1
TBX1 Chr22:19743735 c.-620A>C NM_080647.1 rs536892777
TIMM8A ChrX:100601671 c.133-23A>C NM_004085.3 rs869320666
TMC1 Chr9:75315577 c.362+18A>G NM_138691.2
TYR Chr11:88960973 c.1037-18T>G NM_000372.4
UBR1 Chr15:43330355 c.1911+14C>G NM_174916.2
UBR1 Chr15:43350639 c.1094-12A>G NM_174916.2
UBR1 Chr15:43350640 c.1094-13A>G NM_174916.2
UBR1 Chr15:43363136 c.529-13G>A NM_174916.2
USH2A Chr1:215821092 c.14583-20C>G NM_206933.2
USH2A Chr1:215967783 c.9959-4159A>G NM_206933.2
USH2A Chr1:216039721 c.8845+628C>T NM_206933.2
USH2A Chr1:216064540 c.7595-2144A>G NM_206933.2 rs786200928
USH2A Chr1:216247476 c.5573-834A>G NM_206933.2
USH2A Chr1:216592035 c.486-14G>A NM_206933.2 rs374536346
USH2A Chr1:216596610 c.-259G>T NM_206933.2
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed
ABHD5
ACOX1
ACTB
AMMECR1
ANLN
ATP6V0A4
CISD2
EDNRA
EFTUD2
FGFR2
FOXC1
GDF6
GREB1L
HOXA2
KITLG
KMT2D
LHX3
MASP1
MCM2
NDRG1
NEFL
NF2
NOG
NR2F1
OPA1
PAX1
PCGF2
PEX11B
PEX12
PEX13
PEX14
PEX2
PEX5
PEX7
PHYH
PMP22
PTPRQ
RAI1
REST
ROR1
SERAC1
SH3TC2
SIX2
SLC44A4
SLC4A11
TBX1
TMEM126A
TRRAP
UBR1

Test Strengths

The strengths of this test include:

  • CAP accredited laboratory
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • Our rigorous variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test Limitations

Variants in the KCNE1 gene should not be used for risk assessment at the moment. Specifically, KCNE1 c.253G>A, p.(Asp85Asn) variant has been considered to be a mild risk factor for acquired long QT syndrome. However, in the newest version of the reference genome GRCh38, a gene KCNE1B, nearly identical to KCNE1 has appeared. By using standard NGS technologies, as well as Sanger sequencing, it is not possible to get reliable region-specific sequences for these genes. It is likely that reads that have been earlier mapped to KCNE1 actually belong to KCNE1B. Moreover, it is currently unclear whether KCNE1B produces a protein product, and if a protein is produced, whether the gene is expressed in heart. More independent data characterizing KCNE1B and its function are needed. Currently, all KCNE1 sequence data and the literature related to KCNE1 variants should be interpreted with caution.

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: OTOA (NM_144672:22-27), PDZD7 (NM_024895:10), POLR1C (NM_001318876:9), STRC (NM_153700:1-18). Note that we are able to detect variant in exons 19-29 of STRC, but our abilities are limited due to the high degree of homology that is shared between these exons and other regions of the genome. Whole gene deletions of STRC can and have been detected.

Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

The performance metrics listed below are from an initial validation performed at our main laboratory in Finland. The performance metrics of our laboratory in Seattle, WA, are equivalent.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999%
Insertions, deletions and indels by sequence analysis
1-10 bps 99.2% (7,745/7,806) >99.9999%
11-50 bps 99.13% (2,524/2,546) >99.9999%
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (25/25)
     
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
     
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%


Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %
ANALYTIC VALIDATION (NA samples; n=4)
Single nucleotide variants
Heteroplasmic (45-100%) 100.0% (50/50) 100.0%
Heteroplasmic (35-45%) 100.0% (87/87) 100.0%
Heteroplasmic (25-35%) 100.0% (73/73) 100.0%
Heteroplasmic (15-25%) 100.0% (77/77) 100.0%
Heteroplasmic (10-15%) 100.0% (74/74) 100.0%
Heteroplasmic (5-10%) 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 50.0% (2/4) 100.0%
CLINICAL VALIDATION (n=76 samples)
All types
Single nucleotide variants n=2026 SNVs
Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%
Heteroplasmic (35-45%) 100.0% (4/4) 100.0%
Heteroplasmic (25-35%) 100.0% (3/3) 100.0%
Heteroplasmic (15-25%) 100.0% (3/3) 100.0%
Heteroplasmic (10-15%) 100.0% (9/9) 100.0%
Heteroplasmic (5-10%) 92.3% (12/13) 99.98%
Heteroplasmic (<5%) 88.9% (48/54) 99.93%
Insertions and deletions by sequence analysis n=40 indels
Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%
Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%
SIMULATION DATA /(mitomap mutations)
Insertions, and deletions 1-24 bps by sequence analysis; n=17
Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%
Heteroplasmic (50%) 100.0% (17/17) 99.99%
Heteroplasmic (25%) 100.0% (17/17) 100.0%
Heteroplasmic (20%) 100.0% (17/17) 100.0%
Heteroplasmic (15%) 100.0% (17/17) 100.0%
Heteroplasmic (10%) 94.1% (16/17) 100.0%
Heteroplasmic (5%) 94.1% (16/17) 100.0%
Copy number variants (separate artifical mutations; n=1500)
Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%
Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%
The performance presented above reached by following coverage metrics at assay level (n=66)
Mean of medians Median of medians
Mean sequencing depth MQ0 (clinical) 18224X 17366X
Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%
rho zero cell line (=no mtDNA), mean sequencing depth 12X

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding and regulatory variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases including, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as  SIFT, PolyPhen,MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists, and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the cornerstone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.

The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing or by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes, and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene, and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts, and detailed information about related phenotypes. We also provide links to the references, abstracts, and variant databases used to help ordering providers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. Our laboratory is therefore well-positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering healthcare provider at no additional cost, according to our latest follow-up reporting policy.

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